Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study.

Author(s): Josep Tabernero, Gerald W. Prager, Marwan Fakih, Fortunato Ciardiello, Eric Van Cutsem, Elena Elez, Felipe Melo Cruz, Lucjan Wyrwicz, Daniil Stroyakovskiy, Zsuzsanna Papai, Pierre-guillaume Poureau, Gabor Liposits, Chiara Cremolini, Igor Bondarenko, Dominik Paul Modest, Karim A. Benhadji, Ronan Fougeray, Catherine Leger, Nadia Amellal, Julien Taieb

Source: J Clin Oncol 41, 2023 (suppl 4; abstr 4) 10.1200/JCO.2023.41.3_suppl.4

Dr. Anjan Patel's Thoughts

In the SUNLIGHT study, Lonsurf + bevacizumab was found to be superior to bevacizumab alone in the 3L setting of mCRC, independent of mutation status. First 3L mCRC where the control group was an active compound instead of a placebo. OS was superior, with a clinically meaningful difference of 10.8 vs. 7.5 months. This is now the SOC 3L option in mCRC, in my opinion.

BACKGROUND

Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (Bev) demonstrated promising efficacy in a randomized phase 2 trial of heavily pretreated patients (pts) with metastatic colorectal cancer (mCRC). SUNLIGHT was conducted to confirm these findings.

METHODS

The global phase 3 SUNLIGHT study enrolled pts aged ≥18 years with histologically confirmed mCRC, ECOG PS 0/1, and treated with 1-2 prior chemotherapy regimens in an advanced setting, including fluoropyrimidines, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody (if medically considered) and/or anti-EGFR monoclonal antibody for RAS wild-type tumors. Pts were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) alone or combined with Bev (5 mg/kg on days 1 and 15). Primary endpoint was overall survival (OS).

RESULTS

Between Nov 2020 and Feb 2022, 492 pts were randomised to receive FTD/TPI + Bev (n = 246) or FTD/TPI (n = 246). Baseline characteristics were balanced between arms. FTD/TPI + Bev significantly extended OS over FTD/TPI, median OS was 10.8 months vs 7.5 months, respectively (HR, 0.61; 95% CI, 0.49, 0.77; P< 0.001). OS rates at 12 months were 43% in the FTD/TPI + Bev arm and 30% in the FTD/TPI arm. Median progression-free survival was 5.6 months in the FTD/TPI + Bev arm and 2.4 months in the FTD/TPI arm (HR, 0.44; 95% CI, 0.36,0.54; P< 0.001). Grade ≥3 adverse events (AEs) were not significantly increased in the FTD/TPI + Bev arm vs the FDT/TPI arm (72.4% vs 69.5%). No new safety signals were noted.

CONCLUSIONS

FTD/TPI + Bev provided a statistically significant and a clinically meaningful 3.3-month improvement in OS, extending mOS up to 10.8 months, with a 39% reduction in the HR of death in pts with refractory mCRC and with a predictable and acceptable safety profile. Clinical trial information: NCT04737187.

Author Affiliations

Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain; , Medical University of Vienna, Vienna, Austria; , City of Hope National Comprehensive Cancer Center, Duarte, CA; , Precision Medicine Department, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy; , Department of Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Herent, Belgium; , Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), UVic-UCC, Barcelona, Spain; , Núcleo de Pesquisa e Ensino da Rede São Camilo, Sao Paulo, Brazil; , Department of Oncology and Radiotherapy, Maria Sklodowska-Curie National Cancer Research Institute, Warsaw, Poland; , Moscow City Oncological Hospital #62, Moscow Area, Russian Federation; , Medical Oncology, Duna Medical Centre, Budapest, Hungary; , Institut de Cancérologie, Brest, France; , Department of Clinical Research, University of Southern Denmark, Odense, Denmark; , Department of Translational Research and New Technologies, University of Pisa, Pisa, Italy; , Department of Oncology and Medical Radiology; Dnipropetrovsk Medical Academy, Dnipro, Ukraine; , Charité Universitätsmedizin Berlin, Berlin, Bagun, Germany; , Taiho Oncology, Inc., Princeton, NJ; , Servier International Research Institute, Suresnes, France; , Université Paris-Cité, (Paris Descartes), Georges Pompidou European Hospital, SIRIC CARPEM, Paris, France;

Nivolumab plus Ipilimumab in Microsatellite-Instability–High Metastatic Colorectal Cancer

Here is a large phase-III well done study confirming what we knew from earlier studies, that ipilimumab plus nivolumab (Ipi+Nivo) is highly active and effective in the microsatellite instability-high metastatic colorectal cancer (MSI-high met-CRC) population. This is most likely more effective than single agent IO therapy but with higher rates of toxicity. When all things are equal, I would consider this to be the standard of care (SOC) in this context.

Oxaliplatin Added to Fluoropyrimidine/Bevacizumab as Initial Therapy for Unresectable Metastatic Colorectal Cancer in Older Patients: A Multicenter, Randomized, Open-Label Phase III Trial (JCOG1018)

This Japanese study showed no benefit with the addition of oxaliplatin to fluoropyrimidine plus bevacizumab (5FU+bev) in patients who were aged 70-74 but unfit, or >=75. Interestingly survival was actually shorter in the patients who received oxaliplatin at 21.3 vs 19.7 months.

Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study

Overall survival (OS) improvement was not statistically significant in the study arm but is a non-chemotherapy option. Patients here had tumors with MSS.

Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study

Less maintenance is NOT NON-inferior, so it is inferior in patients with wild type BRAF metastatic colon cancer. So it is better to keep on the full regimen. Although, quality of life is better.

A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening

Colorectal cancer screening by peripheral blood testing? This cell-free DNA assay had an 83% sensitivity and 90% specificity for advanced neoplasia. However, the issue is that this does not detect precancerous lesions well. Colonoscopy has its obvious advantages as it can both diagnose colorectal cancer as well as eradicate precancerous lesions.